This is an application for a K23 Mentored Patient-Oriented Research Career Development Award entitled "Glutamatergic Mediators of Antidepressant Response in Major Depression". The candidate has a background in the clinical management of mood disorders and training in clinical trial methodology and is currently the Associate Director for Translational Neuroscience Research in the Biological Psychiatry Laboratory at McLean Hospital. The current proposal is designed to enable the candidate to gain experience and training in the use of magnetic resonance spectroscopy (MRS) as an in vivo neuroimaging tool to be used adjunctively with clinical trials to measure neurochemical changes associated with treatment. In doing so, the candidate hopes to be able to identify mediators of treatment response to standard and novel treatments for mood disorders and to better understand the mechanisms of action of these treatments. Through the proposed research, interactions with mentors and consultants, and didactic coursework, the candidate seeks to obtain specialized training and experience in: 1) advanced clinical trial methodology and biostatistics;2) MRS techniques and their applications to clinical psychiatric research;3) principles of neurochemistry;and 4) the responsible conduct of research. Exposure to the large neuroscience research community at McLean as well as access to a large clinical population at McLean and unlimited access to the McLean Brain Imaging Center provides the candidate with the ideal environment to carry out this work. This training will foster the candidate's development into an independent clinical investigator using MRS to elucidate the mechanism of action of mood disorder treatments with a focus on the identification of potential neurochemical biomarkers of treatment response. The proposed research uses a novel MRS technique, J-resolved proton MRS, to measure acute and chronic changes in brain levels of glutamate and glutamine in depressed patients with major depressive disorder (MDD) following treatment with citalopram while simultaneously assessing depressive symptoms as measured by the 21-item Hamilton Depression Rating Scale (HAM-D). Specifically, the candidate proposes to treat 25 depressed MDD patients with citalopram 20-60 mg daily for a period of 6 weeks. During the course of the study, the candidate will perform a total of 4 MRS scans occurring at: 1) baseline;2) day 3 of treatment;3) day 7 of treatment;and 4) week 6 of treatment. Clinical assessments will be performed weekly during the course of the study. The primary aim is to test the hypothesis that citalopram treatment is associated with an increase in the glutamine/glutamate ratio (Gln/Glu), an index of glutamatergic neurotransmitter activity, in the anterior cingulate cortex (ACC) from baseline to day 3 of treatment. The secondary aim is to test the hypothesis that citalopram treatment is associated with an increase in the Gln/Glu ratio in the ACC from baseline to day 7 of treatment. Exploratory aims will investigate whether: 1) citalopram treatment is associated with no change in the Gln/Glu ratio in the ACC from baseline to week 6 of treatment;2) change in the Gln/Glu ratio in the ACC from baseline to day 3 is positively associated with improvement in depressive symptoms at week 6;3) change in the Gln/Glu ratio in the ACC from baseline to day 7 is positively associated with improvement in depression symptoms at week 6;and 4) the Gln/Glu ratio at baseline is positively associated with improvement in depressive symptoms at week 6. In doing so, the candidate hopes to identify early changes in glutamatergic activity following citalopram treatment that may mediate clinical response. MDD is a common and often debilitating disorder. Despite this, a significant fraction of MDD patients do not respond to currently available treatments and many others must endure multiple medication trials before an effective treatment can be identified. The proposed project would have major significance for several reasons. First, it will further elucidate the mechanism of action of selective serotonin reuptake inhibitors (SSRIs), and perhaps other standard antidepressant medications, facilitating the future development of novel MDD treatments. Second, if early changes in the Gln/Glu ratio are shown to mediate clinical response, this evidence would support further investigation of the Gln/Glu ratio as a biomarker that may predict treatment response to citalopram, and perhaps other antidepressant treatments. Given the time presently required for an adequate trial of existing antidepressants, and the frequent need for multiple trials to achieve response, it would be a major advance to find a biomarker able to predict clinical response early in the treatment of MDD. Third, this study will likely provide additional insights into the role of glutamatergic dysfunction in mood disorders, expanding scientific knowledge of the pathophysiology and potential treatment of MDD. PUBLIC HEALTH RELEVANCE: Major depressive disorder (MDD) is a common, chronic, and debilitating mental illness that represents a significant public health problem. However, our understanding of the mechanism of action of currently available antidepressant treatments is limited making it difficult to develop newer, more effective, treatments. This study will use a novel neuroimaging technique to investigate whether treatment with the antidepressant citalopram is associated with acute changes in the neurotransmitter glutamate in individuals with MDD and whether these changes are associated with clinical response.